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The SARS\u2010CoV\u20102 main protease (Mpro) is one of the main targets for drug design due to its key role in the virus replication and its distinguished ability to cleave peptides after a glutamine residue. Inspired by the knowledge of the inhibition mechanism of 20S Proteasome, this work focuses on exploring the inhibition process of SARS\u2010CoV\u20102 M\n                    <jats:sup>pro<\/jats:sup>\n                    with a \u03b2\u2010lactone, as well as the impact of the stereochemistry of this compound on the stability of the enzyme:inhibitor binding formation complex. Based on molecular dynamics simulations with classical and hybrid QM\/MM potentials, the free energy landscape of the mechanism of the formation of the covalent complex has been computed. The results show how one of the stereoisomers of the \u03b2\u2010lactone derivative forms a stable reactant non\u2010covalent complex in the active site of M\n                    <jats:sup>pro<\/jats:sup>\n                    . Analysis of the kinetics and thermodynamics of the inhibition process suggests that this non\u2010peptidyl compound can be considered a lead compound for future developments of efficient therapeutic compounds to treat patients with COVID\u201019.\n                  <\/jats:p>","DOI":"10.1002\/pro.70680","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:03:13Z","timestamp":1781845393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The pivotal role of \u03b2\u2010lactone stereochemistry in the development of\n                    <scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102 M\n                    <sup>pro<\/sup>\n                    inhibitors"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7528-1551","authenticated-orcid":false,"given":"Katarzyna","family":"\u015awiderek","sequence":"first","affiliation":[{"name":"BioComp Group Institute of Advanced Materials, INAM, Universitat Jaume I  Castell\u00f3 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3665-3391","authenticated-orcid":false,"given":"Vicent","family":"Moliner","sequence":"additional","affiliation":[{"name":"BioComp Group Institute of Advanced Materials, INAM, Universitat Jaume I  Castell\u00f3 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC06195F"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2025.118247"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.4c03654"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC03628A"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.2c00152"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00124a002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.65.070196.004101"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-020-00161-6"},{"key":"e_1_2_9_10_1","volume-title":"Discovery Studio Visualizer, version 19.0","author":"Dassault Syst\u00e8mes BIOVIA","year":"2019"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c21421"},{"key":"e_1_2_9_12_1","first-page":"686","article-title":"The ubiquitin\u2010proteasome system as a drug target in cerebrovascular disease: therapeutic potential of proteasome inhibitors","volume":"6","author":"Di Napoli M","year":"2005","journal-title":"Curr Opin Investig Drugs"},{"key":"e_1_2_9_13_1","first-page":"333","article-title":"MLN\u2010519. 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